Cardiac-specific PFKFB3 overexpression prevents diabetic cardiomyopathy via enhancing OPA1 stabilization mediated by K6-linked ubiquitination.

Diabetic cardiomyopathy (DCM) is a prevalent complication of type 2 diabetes (T2D). 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a glycolysis regulator. However, the potential effects of PFKFB3 in the DCM remain unclear. In comparison to db/m mice, PFKFB3 levels decreased in the hearts of db/db mice. Cardiac-specific PFKFB3 overexpression inhibited myocardial oxidative stress and cardiomyocyte apoptosis, suppressed mitochondrial fragmentation, and partly restored mitochondrial function in db/db mice. Moreover, PFKFB3 overexpression stimulated glycolysis. Interestingly, based on the inhibition of glycolysis, PFKFB3 overexpression still suppressed oxidative stress and apoptosis of cardiomyocytes in vitro, which indicated that PFKFB3 overexpression could alleviate DCM independent of glycolysis. Using mass spectrometry combined with co-immunoprecipitation, we identified optic atrophy 1 (OPA1) interacting with PFKFB3. In db/db mice, the knockdown of OPA1 receded the effects of PFKFB3 overexpression in alleviating cardiac remodeling and dysfunction. Mechanistically, PFKFB3 stabilized OPA1 expression by promoting E3 ligase NEDD4L-mediated atypical K6-linked polyubiquitination and thus prevented the degradation of OPA1 by the proteasomal pathway. Our study indicates that PFKFB3/OPA1 could be potential therapeutic targets for DCM.

SGLT2 inhibition, plasma proteins, and heart failure: a proteome-wide Mendelian Randomization and colocalization study.

Objective: To investigate the causal contributions of Sodium-glucose cotransporter 2 (SGLT2) inhibition on Heart Failure (HF) and identify the circulating proteins that mediate SGLT2 inhibition's effects on HF. Methods: Applying a two-sample, two-step Mendelian Randomization (MR) analysis, we aimed to estimate: (1) the causal impact of SGLT2 inhibition on HF; (2) the causal correlation of SGLT2 inhibition on 4,907 circulating proteins; (3) the causal association of SGLT2 inhibition-driven plasma proteins on HF. Genetic variants linked to SGLT2 inhibition derived from the previous studies. The 4,907 circulating proteins were derived from the deCODE study. Genetic links to HF were obtained through the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium. Results: SGLT2 inhibition demonstrated a lower risk of HF (odds ratio [OR] = 0.44, 95% CI [0.26, 0.76], P = 0.003). Among 4,907 circulating proteins, we identified leucine rich repeat transmembrane protein 2 (LRRTM2), which was related to both SGLT2 inhibition and HF. Mediation analysis revealed that the impact of SGLT2 inhibition on HF operates indirectly through LRRTM2 [ß = -0.20, 95% CI (-0.39, -0.06), P = 0.02] with a mediation proportion of 24.6%. Colocalization analysis provided support for the connections between LRRTM2 and HF. Conclusion: The study indicated a causative link between SGLT2 inhibition and HF, with plasma LRRTM2 potentially serving as a mediator.

SGLT2 inhibition, circulating proteins, and insomnia: A mendelian randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) initially emerged as oral antidiabetic medication but were subsequently discovered to exhibit pleiotropic actions. Insomnia is a prevalent and debilitating sleep disorder. To date, the causality between SGLT2 inhibitors and insomnia remains unclear. This study aims to evaluate the causality between SGLT2 inhibitors and insomnia and identify potential plasma protein mediators. METHODS: Using a two-sample Mendelian Randomization (MR) analysis, we estimated the causality of SGLT2 inhibition on insomnia and sleep duration. Additionally, employing a two-step and proteome-wide MR analysis, we evaluated the causal link of SGLT2 inhibition on 4907 circulating proteins and the causality of SGLT2 inhibition-driven plasma proteins on insomnia. We applied a false discovery rate (FDR) correction for multiple comparisons. Furthermore, mediation analyses were used to identify plasma proteins that mediate the effects of SGLT2 inhibition on insomnia. RESULTS: SGLT2 inhibition was negatively correlated with insomnia (odds ratio [OR] = 0.791, 95 % confidence interval [CI] [0.715, 0.876], P = 5.579*10^-6) and positively correlated with sleep duration (ß = 0.186, 95 % CI [0.059, 0.314], P = 0.004). Among the 4907 circulating proteins, diadenosine tetraphosphatase (Ap4A) was identified as being linked to both SGLT2 inhibition and insomnia. Mediation analysis indicated that the effect of SGLT2 inhibition on insomnia partially operates through Ap4A (ß = -0.018, 95 % CI [-0.036, -0.005], P = 0.023), with a mediation proportion of 7.7 %. CONCLUSION: The study indicated a causality between SGLT2 inhibition and insomnia, with plasma Ap4A potentially serving as a mediator.

APOB and CCL17 as mediators in the protective effect of SGLT2 inhibition against myocardial infarction: Insights from proteome-wide mendelian randomization.

AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors offer a novel therapeutic avenue for myocardial infarction (MI). However, the exact nature of this relationship and the underlying mechanisms are not fully understood. METHODS: Utilizing a two-sample Mendelian Randomization (MR) analysis, we elucidated the causal effects stemming from the inhibition of SGLT2 on MI. Then, The pool of 4907 circulating proteins within the plasma proteome were utilized to explore the mediators of SGLT2 inhibitors on MI. Protein-protein network and enrichment analysis were conducted to clarify the potential mechanism. Finally, employing MR analysis and meta-analysis techniques, we systematically assessed the causal associations between SGLT2 inhibition and coronary heart diseases (CHD). RESULTS: SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of MI (odds ratio [OR] = 0.462, [95% CI 0.222, 0.958], P = 0.038). Among 4907 circulating proteins, we identified APOB and CCL17 which were related to both SGLT2 inhibition and MI. Mediation analysis showed evidence of the indirect effect of SGLT2 inhibition on MI through APOB (ß = -0.557, 95%CI [-1.098, -0.155]) with a mediated proportion of 72%, and CCL17 (ß = -0.176, 95%CI [-0.332, -0.056]) with a mediated proportion of 17%. The meta-analysis result showed that SGLT2 inhibition was associated with a lower risk of CHD. CONCLUSION: Based on proteome-wide mendelian randomization, APOB and CCL17 were seen as mediators in the protective effect of SGLT2 inhibition against myocardial infarction.

Long term survival outcomes of surgery combined with hyperthermic intraperitoneal chemotherapy for perforated low-grade appendiceal mucinous neoplasms: A multicenter retrospective study.

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are very rare, accounting for approximately 0.2%-0.5% of gastrointestinal tumors. We conducted a multicenter retrospective study to explore the impact of different surgical procedures combined with HIPEC on the short-term outcomes and long-term survival of patients. METHODS: We retrospectively analyzed the clinicopathological data of 91 LAMN perforation patients from 9 teaching hospitals over a 10-year period, and divided them into HIPEC group and non-HIPEC group based on whether or not underwent HIPEC. RESULTS: Of the 91 patients with LAMN, 52 were in the HIPEC group and 39 in the non-HIPEC group. The Kaplan-Meier method predicted that 52 patients in the HIPEC group had 5- and 10-year overall survival rates of 82.7% and 76.9%, respectively, compared with predicted survival rates of 51.3% and 46.2% for the 39 patients in the non-HIPEC group, with a statistically significant difference between the two groups (χ2 = 10.622, p = 0.001; χ2 = 10.995, p = 0.001). Compared to the 5-year and 10-year relapse-free survival rates of 75.0% and 65.4% in the HIPEC group, respectively, the 5-year and 10-year relapse-free survival rates of 48.7% and 46.2% in the non-HIPEC group were significant different between the two outcomes (χ2 = 8.063, p = 0.005; χ2 = 6.775, p = 0.009). The incidence of postoperative electrolyte disturbances and hypoalbuminemia was significantly higher in the HIPEC group than in the non-HIPEC group (p = 0.023; p = 0.044). CONCLUSIONS: This study shows that surgery combined with HIPEC can significantly improve 5-year and 10-year overall survival rates and relapse-free survival rates of LAMN perforation patients, without affecting their short-term clinical outcomes.

CAV3 alleviates diabetic cardiomyopathy via inhibiting NDUFA10-mediated mitochondrial dysfunction.

BACKGROUND: The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated. METHODS: Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and functional experiments. RESULTS: Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10. CONCLUSIONS: The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.

Overexpression of BRD4 in Gastric Cancer and its Clinical Significance as a Novel Therapeutic Target.

BACKGROUND: BRD4 is a member of the bromodomain and extra terminal domain (BET) family of proteins, containing two bromodomains and one extra terminal domain, and is overexpressed in several human malignancies. However, its expression in gastric cancer has not yet been well illustrated. OBJECTIVE: This study aimed to elucidate the overexpression of BRD4 in gastric cancer and its clinical significance as a novel therapeutic target. METHODS: Fresh gastric cancer tissues and paraffin-embedded specimens of gastric cancer patients were collected, and the BRD4 expression was examined by Western Blot Analysis (WB) and Immunohistochemistry Analysis (IHC), respectively. The possible relationship between BRD4 expression and the clinicopathological features as well as survival in gastric cancer patients was analyzed. The effect of BRD4 silencing on human gastric cancer cell lines was investigated by MTT assay, WB, wound healing assay, and Transwell invasion. RESULTS: The results showed that the expression level in tumor tissues and adjacent tissues was significantly higher than that in normal tissues, respectively (P < 0.01). BRD4 expression level in gastric cancer tissues was strongly correlated with the degree of tumor differentiated degree (P = 0.033), regional lymph nodes metastasis (P = 0.038), clinical staging (P = 0.002), and survival situation (P = 0.000), while the gender (P = 0.564), age (P = 0.926) and infiltrating depth (P = 0.619) of patients were not associated. Increased BRD4 expression resulted in poor overall survival (P = 0.003). In in vitro assays, BRD4 small interfering RNA resulted in significantly decreased BRD4 protein expression, therefore inhibiting proliferation, migration, and invasion of gastric cancer cells. CONCLUSION: BRD4 might be a novel biomarker for the early diagnosis, prognosis, and therapeutic target in gastric cancer.

Unleashing the Potential of Nrf2: A Novel Therapeutic Target for Pulmonary Vascular Remodeling.

Pulmonary vascular remodeling, characterized by the thickening of all three layers of the blood vessel wall, plays a central role in the pathogenesis of pulmonary hypertension (PH). Despite the approval of several drugs for PH treatment, their long-term therapeutic effect remains unsatisfactory, as they mainly focus on vasodilation rather than addressing vascular remodeling. Therefore, there is an urgent need for novel therapeutic targets in the treatment of PH. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor that regulates endogenous antioxidant defense and emerges as a novel regulator of pulmonary vascular remodeling. Growing evidence has suggested an involvement of Nrf2 and its downstream transcriptional target in the process of pulmonary vascular remodeling. Pharmacologically targeting Nrf2 has demonstrated beneficial effects in various diseases, and several Nrf2 inducers are currently undergoing clinical trials. However, the exact potential and mechanism of Nrf2 as a therapeutic target in PH remain unknown. Thus, this review article aims to comprehensively explore the role and mechanism of Nrf2 in pulmonary vascular remodeling associated with PH. Additionally, we provide a summary of Nrf2 inducers that have shown therapeutic potential in addressing the underlying vascular remodeling processes in PH. Although Nrf2-related therapies hold great promise, further research is necessary before their clinical implementation can be fully realized.

Lentinan alleviates diabetic cardiomyopathy by suppressing CAV1/SDHA-regulated mitochondrial dysfunction.

Diabetic cardiomyopathy (DCM), characterized by mitochondrial dysfunction and impaired energetics as contributing factors, significantly contributes to high mortality in patients with diabetes. Targeting key proteins involved in mitochondrial dysfunction might offer new therapeutic possibilities for DCM. Lentinan (LNT), a ß-(1,3)-glucan polysaccharide obtained from lentinus edodes, has demonstrated biological activity in modulating metabolic syndrome. In this study, the authors investigate LNT's pharmacological effects on and mechanisms against DCM. The results demonstrate that administering LNT to db/db mice reduces cardiomyocyte apoptosis and mitochondrial dysfunction, thereby preventing DCM. Notably, these effects are fully negated by Caveolin-1 (CAV1) overexpression both in vivo and in vitro. Further studies and bioinformatics analysis uncovered that CAV1 bound with Succinate dehydrogenase subunit A (SDHA), triggering the following ubiquitination and degradation of SDHA, which leads to mitochondrial dysfunction and mitochondria-derived apoptosis under PA condition. Silencing CAV1 leads to reduced apoptosis and improved mitochondrial function, which is blocked by SDHA knockdown. In conclusion, CAV1 directly interacts with SDHA to promote ubiquitination and proteasomal degradation, resulting in mitochondrial dysfunction and mitochondria-derived apoptosis, which was depressed by LNT administration. Therefore, LNT may be a potential pharmacological agent in preventing DCM, and targeting the CAV1/SDHA pathway may be a promising therapeutic approach for DCM.

Low-dose lithium adjunct to atypical antipsychotic treatment nearly improved cognitive impairment, deteriorated the gray-matter volume, and decreased the interleukin-6 level in drug-naive patients with first schizophrenia symptoms: a follow-up pilot study.

This study was conducted to investigate the effects of long-term low-dose lithium adjunct to antipsychotic agent use on the cognitive performance, whole-brain gray-matter volume (GMV), and interleukin-6 (IL-6) level in drug-naive patients with first-episode schizophrenia, and to examine relationships among these factors. In this double-blind randomized controlled study, 50 drug-naive patients with first-episode schizophrenia each took low-dose (250 mg/day) lithium and placebo (of the same shape and taste) adjunct to antipsychotic agents (mean, 644.70 ± 105.58 and 677.00 ± 143.33 mg/day chlorpromazine equivalent, respectively) for 24 weeks. At baseline and after treatment completion, the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive performance, 3-T magnetic resonance imaging was performed to assess structural brain alterations, and serum IL-6 levels were quantified by immunoassay. Treatment effects were assessed within and between patient groups. Relationships among cognitive performance, whole-brain GMVs, and the IL-6 level were investigated by partial correlation analysis. Relative to baseline, patients in the lithium group showed improved working memory, verbal learning, processing speed, and reasoning/problem solving after 24 weeks of treatment; those in the placebo group showed only improved working memory and verbal learning. The composite MCCB score did not differ significantly between groups. The whole-brain GMV reduction was significantly lesser in the lithium group than in the placebo group (0.46% vs. 1.03%; P < 0.001). The GMV and IL-6 reduction ratios correlated with each other in both groups (r = -0.17, P = 0.025). In the lithium group, the whole-brain GMV reduction ratio correlated with the working memory improvement ratio (r = -0.15, P = 0.030) and processing speed (r = -0.14, P = 0.036); the IL-6 reduction ratio correlated with the working memory (r = -0.21, P = 0.043) and verbal learning (r = -0.30, P = 0.031) improvement ratios. In the placebo group, the whole-brain GMV reduction ratio correlated only with the working memory improvement ratio (r = -0.24, P = 0.019); the IL-6 reduction ratio correlated with the working memory (r = -0.17, P = 0.022) and verbal learning (r = -0.15, P = 0.011) improvement ratios. Both treatments implemented in this study nearly improved the cognitive performance of patients with schizophrenia; relative to placebo, low-dose lithium had slightly greater effects on several aspects of cognition. The patterns of correlation among GMV reduction, IL-6 reduction, and cognitive performance improvement differed between groups.

NLRP12 downregulates the Wnt/ß-catenin pathway via interaction with STK38 to suppress colorectal cancer.

Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here, we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelial-mesenchymal transition. Signaling pathway analysis revealed higher activation of the Wnt/ß-catenin pathway, but not NF-κB and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12-conditional knockout mice, we revealed that NLRP12 downregulates ß-catenin activation in intestinal epithelial cells, thereby suppressing colorectal tumorigenesis. Consistent with this, Nlrp12-deficient intestinal organoids and CRC cells showed increased proliferation, accompanied by higher activation of ß-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3ß, leading to the degradation of ß-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3ß and ß-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/ß-catenin pathway, and the NLRP12/STK38/GSK3ß signaling axis could be a promising therapeutic target for CRC.

Optimization of the Methods to Develop Stable Polymer Gels for Water Management in Medium- and Ultra-High-Salinity Reservoirs.

Polymer gels suffer from a serious syneresis issue when exposed to high-temperature and high-salinity (HTHS) conditions, which limits their use as water-treatment agents in this type of reservoir. In this paper, the effects of the polymer type/concentration, deoxidizers, and stabilizers on the long-term stability of polymer gels were systematically studied; thus, the methods to develop stable polymer gels for two typical levels of salinity were optimized. The results show the following: (1) For a medium-salinity condition (TDS: 33,645.0 mg/L) at 125 °C, conventional HPAM gels completely dehydrate within only 1 day, and the addition of a deoxidizer hardly improved their stability. Some special polymers, e.g., AP-P5, MKY, and CPAM, are able to form stable gels if a high concentration of 0.8% is used; the syneresis rate of these gels is about 10% after 30 days. However, the addition of the complexant sodium oxalate significantly improves the stability of gels formed by all five of these different polymers, which behave with a 0% syneresis rate after 30 days pass. Complexants are the most economical and feasible agents to develop stable gels in medium-salinity water. (2) Gels enhanced using the methods above all become unstable in a more challenging ultra-high-saline condition (TDS: 225,068.0 mg/L). In this case, special calcium- and magnesium-resistant polymers are required to prepare stable gels, which show 0% syneresis rates after 30 days, have relatively low strengths, but do produce a good plugging effect in high-permeability cores.

Discovery of Podofilox as a Potent cGAMP-STING Signaling Enhancer with Antitumor Activity.

Cyclic GMP-AMP (cGAMP) is a second messenger that activates the stimulator of interferon genes (STING) innate immune pathway to induce the expression of type I IFNs and other cytokines. Pharmacologic activation of STING is considered a potent therapeutic strategy in cancer. In this study, we used a cell-based phenotypic screen and identified podophyllotoxin (podofilox), a microtubule destabilizer, as a robust enhancer of the cGAMP-STING signaling pathway. We found that podofilox enhanced the cGAMP-mediated immune response by increasing STING-containing membrane puncta and the extent of STING oligomerization. Furthermore, podofilox changed the trafficking pattern of STING and delayed trafficking-mediated STING degradation. Importantly, the combination of cGAMP and podofilox had profound antitumor effects on mice by activating the immune response through host STING signaling. Together, these data provide insights into the regulation of cGAMP-STING pathway activation and demonstrate what we believe to be a novel approach for modulating this pathway and thereby promoting antitumor immunity.

A Study on the Transnational Spillover Effects of Bank Risk and Sovereign Risk-From the Perspective of COVID-19 Epidemic Situation.

In recent years, the world economy and the global financial system have closely intertwined, deepened economic and financial integration via cross-border investments, financings, imports, and exports. Since banks serve as the core of a country's financial system, the risk status of banks directly affects the country's national credit and financial security. The current complexities of the international and domestic environments are increasing geopolitical risks. Moreover, there is increasing uncertainty recognition in the financial and economic development of all countries, more systemic banking risks, and sovereign risk transfer elements. In this scenario, resisting external risk input is essential to enhance risk prevention ability. Therefore, this paper adopted the VAR-based time domain and frequency model for a multi-dimensional analysis of the two perspectives of banking and sovereign risk spillover effects. The empirical results indicate that the entire sample under the static overflow effect always shows that most of the absorption is the banking sector risk, and sovereign risk is the leading risk spillover. In the frequency domain perspective, the short-term spillover effects between bank and sovereign risk are dominant. Moreover, in relation to the outbreak and continuous spread of the COVID-19 pandemic, the spillover effects are often dominated by adverse, long-term scenarios.

LL-37 transports immunoreactive cGAMP to activate STING signaling and enhance interferon-mediated host antiviral immunity.

Cyclic 2',3'-GMP-AMP (cGAMP) binds to and activates stimulator of interferon genes (STING), which then induces interferons to drive immune responses against tumors and pathogens. Exogenous cGAMP produced by infected and malignant cells and synthetic cGAMP used in immunotherapy must traverse the cell membrane to activate STING in target cells. However, as an anionic hydrophilic molecule, cGAMP is not inherently membrane permeable. Here, we show that LL-37, a human host defense peptide, can function as a transporter of cGAMP. LL-37 specifically binds cGAMP and efficiently delivers cGAMP into target cells. cGAMP transferred by LL-37 activates robust interferon responses and host antiviral immunity in a STING-dependent manner. Furthermore, we report that LL-37 inducers vitamin D3 and sodium butyrate promote host immunity by enhancing endogenous LL-37 expression and its mediated cGAMP immune response. Collectively, our data uncover an essential role of LL-37 in innate immune activation and suggest new strategies for immunotherapy.

AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells.

Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.

Tough, Highly Oriented, Super Thermal Insulating Regenerated All-Cellulose Sponge-Aerogel Fibers Integrating a Graded Aligned Nanostructure.

Thermal insulating fibers can effectively regulate the human body temperature and decrease indoor energy consumption. However, designing super thermal insulating fibers integrating a sponge and aerogel structure based on biomass resources is still a challenge. Herein, a flow-assisted dynamic dual-cross-linking strategy is developed to realize the steady fabrication of regenerated all-cellulose graded sponge-aerogel fibers (CGFs) in a microfluidic chip. The chemically cross-linked cellulose solution is used as the core flow, which is passed through two sheath flow channels, containing either a diffusion solvent or a physical cross-linking solvent, resulting in CGFs with a porous sponge outer layer and a dense aerogel inner layer. By regulating and simulating the flow process in the microfluidic chip, CGFs with adjustable sponge thicknesses, excellent toughness (26.20 MJ m-3), and ultralow thermal conductivity (0.023 W m-1 K-1) are fabricated. This work provides a new method for fabricating graded biomass fibers and inspires attractive applications for thermal insulation in textiles.

Soluble epoxide hydrolase deletion attenuated nicotine-induced arterial stiffness via limiting the loss of SIRT1.

Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2-/-) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide [NAM, sirtuin-1 (SIRT1) inhibitor] simultaneously for 4 wk. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2 knockout mice (Ephx2-/- mice) without NAM treatment. However, the arterial protective effects were gone in Ephx2-/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced matrix metalloproteinase 2 (MMP2) upregulation via SIRT1-mediated yes-associated protein (YAP) deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.NEW & NOTEWORTHY We presently show that sEH knockout repressed nicotine-induced arterial stiffness and extracellular matrix remodeling via SIRT1-induced YAP deacetylation, which highlights that sEH is a potential therapeutic target in smoking-induced arterial stiffness and vascular remodeling.

cGAS restricts colon cancer development by protecting intestinal barrier integrity.

The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingly, mice lacking cGAS were more susceptible to CAC than those lacking stimulator of interferon genes (STING) or type I interferon receptor under the same conditions. cGAS but not STING is highly expressed in intestinal stem cells. cGAS deficiency led to intestinal stem cell loss and compromised intestinal barrier integrity upon dextran sodium sulfate-induced acute injury. Loss of cGAS exacerbated inflammation, led to activation of STAT3, and accelerated proliferation of intestinal epithelial cells during CAC development. Mice lacking cGAS also accumulated myeloid-derived suppressive cells within the tumor, displayed enhanced Th17 differentiation, but reduced interleukin (IL)-10 production. These results indicate that cGAS plays an important role in controlling CAC development by defending the integrity of the intestinal mucosa.

Inhibition of soluble epoxide hydrolase alleviates insulin resistance and hypertension via downregulation of SGLT2 in the mouse kidney.

The epoxyeicosatrienoic acid (EET) exerts beneficial effects on insulin resistance and/or hypertension. EETs could be readily converted to less biological active diols by soluble epoxide hydrolase (sEH). However, whether sEH inhibition can ameliorate the comorbidities of insulin resistance and hypertension and the underlying mechanisms of this relationship are unclear. In this study, C57BL/6 mice were rendered hypertensive and insulin resistant through a high-fat and high-salt (HF-HS) diet. The sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), was used to treat mice (1 mg/kg/day) for 8 weeks, followed by analysis of metabolic parameters. The expression of sEH and the sodium-glucose cotransporter 2 (SGLT2) was markedly upregulated in the kidneys of mice fed an HF-HS diet. We found that TPPU administration increased kidney EET levels, improved insulin resistance, and reduced hypertension. Furthermore, TPPU treatment prevented upregulation of SGLT2 and the associated increased urine volume and the excretion of urine glucose and urine sodium. Importantly, TPPU alleviated renal inflammation. In vitro, human renal proximal tubule epithelial cells (HK-2 cells) were used to further investigate the underlying mechanism. We observed that 14,15-EET or sEH knockdown or inhibition prevented the upregulation of SGLT2 upon treatment with palmitic acid or NaCl by inhibiting the inhibitory kappa B kinase α/ß/NF-κB signaling pathway. In conclusion, sEH inhibition by TPPU alleviated insulin resistance and hypertension induced by an HF-HS diet in mice. The increased urine excretion of glucose and sodium was mediated by decreased renal SGLT2 expression because of inactivation of the inhibitory kappa B kinase α/ß/NF-κB-induced inflammatory response.